Tuberculosis is the leading AIDS associated opportunistic infection found in non-industrialized nations of the world. There is an urgent need to develop new, potent, fast acting anti-tuberculosis drugs that can be used in conjunction with drugs used to treat HIV infections. Towards these ends we propose to explore and develop a novel class of nitrofuranyl amides as new anti-tuberculosis agents. This series of compounds is particularly attractive for TB drug development because of its ease of synthesis allowing for rapid synthesis of analogs in this proposal and could ultimately lead to an inexpensive drug. The goals of this proposal are to enhance the activity of the series in vitro and in vivo and to produce viable preclinical drug candidates. Computational drug design methods and modern medicinal chemistry synthesis techniques will be used to design and synthesize further compound generations. A complete microbiological and biochemical assessment of the nitrofuranyl series will be performed. MIC and MBC determinations for the new generations of compounds will be determined against various M. tuberculosis strains including H37Rv and multidrug resistant tuberculosis. The resistance frequency of M. tuberculosis to the lead compounds will be examined and cross resistance to other anti-tuberculosis drugs will be investigated. Synergy tests will be performed with other anti-tuberculosis drugs and the cytotoxicity of the compounds determined. The mechanism of action of these inhibitors will be studied. The effectiveness of the leads against latent tuberculosis will be evaluated using an in vitro assay of M. tuberculosis grown under low oxygen conditions. Maximum tolerated dose assays and basic bioavailability assays will be performed on the lead compounds. Compounds with good pharmacological profiles will then be tested using a rapid in vivo model. The in vivo activity is then confirmed using the standard TB mouse model. The basic pharmacokinetic and biopharmaceutic properties of leads will be characterized in vivo.
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